Cellular senescence is the process by which cells undergo a permanent and irreversible cell cycle arrest. Several stimuli can induce senescence including telomere attrition, DNA damage, excessive mitogenic stimulation, and activated onco-proteins. Thus, senescence, like apoptosis, is a cellular defense against the proliferation of damaged or mutated cells. Although evading the senescence program is a likely component of tumorigenesis, relatively little is known about this important mechanism. Recently, several reports have demonstrated that the retinoblastoma protein (pRb), through the formation of heterochromatin, is crucial for senescence. Therefore, in a series of novel experiments, we will extensively dissect the phenomenon of senescence with a particular focus on RB proteins. First, we will identify RB target genes silenced during senescence using genomic location analysis and gene expression profiling. Next, we will confirm the crucial function of the pRb protein in senescence-specific gene silencing by acute ablation of pRb in senescent cells. And lastly, we will attempt to discover the molecular mechanism of RB-mediated gene silencing during senescence by an extensive examination of chromatin structure at RB-target genes.